Depentyl analogues of PGA1

ABSTRACT

Depentyl analogues of prostaglandins A, E, and F having no C-16 to C-20 carbon atoms. The analogues correspond to the formula ##STR1## wherein: L is methylene, ethylene, or trimethylene; 
     K is ethylene or cis-vinylene; 
     M is carbonyl, α-hydroxymethylene, or β-hydroxymethylene; 
     N is methylene or methine, provided that N is methine only if P is methine and M is carbonyl; 
     P is methylene, ethylene, α-hydroxymethylene or methine, provided that P is methine only if N is methine; and, 
     R is carboxyl; hydroxymethylene, alkoxycarbonyl, the alkyl portion of said alkoxycarbonyl being a lower alkyl, or a pharmacologically acceptable non-toxic carboxy salt. 
     The analogues are prepared by first converting a trans-1-iodo-3-alkoxy-1-propene to the corresponding lithio compound. This lithio compound then combines with the hexamethylphosphorous triamide complex of copper(I) pentyne to give an alkenylcopper species. Reacting this alkenylcopper compound with the appropriate 2-substituted-cyclopent-2-enone or 2-substituted-cyclohex-2-enone gives the desired depentyl prostaglandins.

This is a division, of application Ser. No. 684,569, filed Feb. 9, 1977.

BACKGROUND OF THE INVENTION 1. Field of the Invention

Compounds of this invention are analogues of natural prostaglandins.

Natural prostaglandins are twenty-carbon atom alicyclic compoundsrelated to prostanoic acid which has the following structure: ##STR2##By convention, the carbon atoms of I are numbered sequentially from thecarboxylic carbon atom. An important sterochemical feature of I is thetrans-orientation of the sidechains C₁ -C₇ and C₁₃ -C₂₀. All naturalprostaglandins have this orientation. In I, as elsewhere in thisspecification, a dashed line ( - - - ) indicates projection of acovalent bond below a reference plane, such as those formed by thecyclopentyl ring or the bonds of a carbon atom (alpha-configuration),while a wedged line ( ) represents direction above that plane(beta-configuration). Those conventions apply to all compoundssubsequently discussed in this specification.

In one system of nomenclature suggested by N. A. Nelson in J. Med Chem.,17: 911 (1972), prostaglandins are named as derivatives or modificationsof the natural prostaglandins. In a second system, the I.U.P.A.C.(International Union of Pure and Applied Chemistry) system ofnomencluature, prostaglandins are named as substituted heptanoic acids.A third system of nomenclature (also described by Nelson), names allprostaglandins as derivatives or modifications of prostanoic acid(structure I) or prostane (the hydrocarbon equivalent of structure I).The latter system is used by Chemical Abstracts.

Natural prostaglandins have the general structure, ##STR3## in which Land M may be ethylene or cis-vinylene radicals five-membered ring##STR4##

Prostaglandins are classified according to the functional groups presentin the five-membered ring and the presence of double bonds in the ringor chains. Prostaglandins of the A-class (PGA or prostaglandin A) arecharacterized by an oxo group at C₉ and a double bond at C₁₀ -C₁₁(Δ¹⁰,11); those of the B-class (PGB) have an oxo group at C₉ and adouble bond at C₈ -C₁₂ (Δ⁸,12); compounds of the C-class (PGC) containan oxo group at C₉ and a double bond at C₁₁ -C₁₂ (Δ¹¹,12); members ofthe D-class (PGD) have an oxo group at C₁₁ and an alpha-oriented hydroxygroup at C₉ ; prostaglandins of the E-class (PGE) have an oxo group atC₉ and an alpha-oriented hydroxyl group at C₁₁ ; and members of theF.sub.α -class (PGF₆₀) have an alpha-directed hydroxyl group at C₉ andan alpha-oriented hydroxyl group at C₁₁. Within each of the A, B, C, D,E, and F classes of prostaglandins are three subclassifications basedupon the presence of double bonds in the side-chains at C₅ -C₆, C₁₅-C₁₄, or C₁₇ -C₁₈. The presence of a trans-unsaturated bond only at C₁₃-C₁₄ is indicated by the subscript numeral 1; thus, for example, PGE₁(or prostaglandin E₁) denotes a prostaglandin of the E-type (oxo-groupat C₉ and an alpha-hydroxyl at C₁₁) with a trans-double bond at C₁₃-C₁₄. The presence of both a trans-double bond at C₁₃ -C₁₄ and acis-double bond at C₅ -C₆ is denoted by the subscript numeral 2: forexample, PGE₂. Lastly, a trans-double bond at C₁₃ -C₁₄, a cis-doublebond at C₅ -C₆ and a cis-double bond at C₁₇ -C₁₈ is indicated by thesubscript numeral 3; for example, PGE₃. The above notations apply toprostaglandins of the A, B, C, D, and F series as well; however, in thelast, the alpha-orientation of the hydroxyl group at C₉ is indicated bythe subscript Greek letter α after the numerical subscript.

The three systems of nomenclature as they apply to natural PGD₃α areshown below: ##STR5## Nelson system:- Prostaglandin F₃α or PGF₃α(shortened form);

I.u.p.a.c. system:- 7-[3R,5S-Dihydroxy-2S-(3S-hydroxy-1E,5Z-octadienyl)-cyclopent-1R-yl]-5Z-heptenoic acid; and, ChemicalAbstracts system:-(5Z,9α,11α,13E,15S,17Z)-9,11,15-trihydroxyprosta-5,13,17-trien-1-oicacid.

It is important to note that in all natural prostaglandins there is analpha-oriented hydroxyl group at C₁₅. In the Cahn-Ingold-Prelog systemof defining sterochemistry, that C₁₅ hydroxyl group is in theS-configuration. The Cahn-Ingold-Prelog system is used to definestereochemistry of any asymmetric center outside of the carbocyclic ringin all three systems of nomenclature described above. This is incontrast to some prostaglandin literature in which the α,β designationsare used, even at C₁₅.

Various derivatives and analogues of the prostaglandins described abovemay be synthesized. Although these derivatives do not occur as such innature, many of them possess activity related to their parent compounds.Such synthetic derivatives and analogues include the following:

A. 11-Deoxy Derivatives of PGE and PGF Molecules

Formula II represents 11-deoxy PGE and PGF compounds when ##STR6## Inthat formula, and others of this patent specification, a swung dash orserpentine line (˜) denotes a covalent bond which can be either in thealpha-configuration (projecting below the appropriate reference plane)or in the beta-configuration (projecting above the reference plane).

B. PGF.sub.β Molecules.

Formula II represents PGF.sub.β compounds when ##STR7##

C. 9-Deoxy Derivatives of PGE. ##STR8## in Formula II, the formula givesthe 9-deoxy derivatives of PGE.

D. 9-Deoxy-Δ⁹,10 Derivatives of PGE.

Formula II represents the 9-deoxy-Δ⁹,10 PGE compounds when ##STR9##

E. 9α-Homo: and 9α-Homo-11-Deoxy Derivative of PGE and PGF Molecules.

These compounds are given by Formula II when ##STR10## represent,respectively, the 9α-homo-PGE, the 9α-homo-11-deoxy-PGE, the 9α-homo-PGFand the 9α-homo-11-deoxy-PGF compounds.

F. 11α-Homo-Derivatives of PGE, PGF and PGA Molecules.

Replacement of ##STR11## in formula II represents the continuedmolecules. In particular, ##STR12## represent the 11α-homo-derivativesof, respectively, PGE, PGF and PGA.

G. 11-Epi-PGE and PGF Molecules,

Formula II represents the 11-epi-compounds of PGE and PGF respectively,when ##STR13##

H. 8-Iso-, 12-Iso or 8,12-Bis-Iso-(Ent)-Prostaglandins.

The 8-Iso, 12-iso- or 8,12-bis-iso-(ent) compounds are obtained fromFormula II by replacing: ##STR14## The iso modifications of Formula IImay be divided into all of the sub-classes with varying ring oxygenationas described above.

Recent research indicates that prostaglandins appear ubiquitously inanimal tissues. They, as well as many of their synthetic analogues, haveimportant biochemical and physiological effects in a variety ofmammalian systems.

In the endocrine system, for example, experimental evidence indicatesprostaglandins influence the hormone synthesis or release of hormones inthe secretory glands. In rats, PGE₁ and PGE₂ increase the release of thegrowth horomone while PGA₁ increases its synthesis. In sheep, PGE₁ andPGF₁α inhibit ovarian progesterone secretion. In a variety of mammals,PGF₁α and PGF₂α act as luteolytic factors. In mice, PGE₁, PGE₂, andPGF₁α and PGF₁β increase thyroid activity. In hypophysectomized rats,PGE₁, PGE₂ and PGF₁α stimulate stereoidogenesis in the adrenal glands.

In the mammalian male reproductive system, PGE₁ contracts the smoothmuscle of the vas deferens. In the female reproductive system, PGE andPGF.sub.α compounds contract uterine smooth muscle. In general, PGE, PGBand PGA compounds relax in vitro human uterine muscle strips, whilethose of the PGF.sub.α class contact such isolated preparations. PGEcompounds, in general, promote fertility in the female reproductivesystem while PGF₂α has contragestational effects. PGF₂α also appears tobe involved in the mechanism of menstruation. In general, PGE₂ producespotent oxytocic effects in inducing labor, while PGF₂α inducesspontaneous abortions in early pregnancy.

PGF₆₀ and PGE compounds have been isolated from a variety of nervoustissue and they seem to act as neurotransmitters. PGE₁ retards whereasPGF₂α facilitates transmission along motor pathways in the centralnervous system. PGE₁ and PGE₂ reportedly inhibit transmitter releasefrom adrenergic nerve endings in the guinea pig.

Prostaglandins stimulate contraction of gastrointestinal smooth musclein vivo and in vitro. In dogs, PGA₁, PGE₁, and PGE₂ inhibit gastricsecretion. PGA₁ exhibits similar activity in man.

In most mammalian respiratory tracts, PGE and PGF compounds affect invitro preparations of tracheal smooth muscle. Specifically, PGE₁ andPGE₂ relax, while PGF₂α contracts, the smooth muscle. The human lungnormally contains PGE and PGF compounds; consequently, some cases ofbronchial asthma may involve an imbalance in the production ormetabolism of those compounds.

Prostaglandins are involved in certain hematic mechanisms in mammals.PGE₁, for example, inhibits thombogenesis in vitro through its effectson blood platelets.

In a variety of mammalian cardiovascular systems, compounds of the PGEand PGA classes are vasodilators whereas those of the PGF.sub.α Classare vasoconstrictors, by virtue of their action on vascular smoothmuscle.

Prostaglandins naturally appear in the kidney and reverse experimentaland clinical renoprial hypertension.

The prostaglandins and their analogues have broad clinical implications.In obstetrics and gynecology, they may find use in fertility control,treatment of menstrual disorders, the induction of labor, and thecorrection of hormone disorders. In gastroenterology, they may helptreat peptic ulcers and various disorders involving motility, secretion,and absorption in the gastrointestinal tract. They may, in therespiratory area, prove beneficial in the therapy of bronchial asthmaand other diseases involving bronchoconstriction. In hematology, theymay display utility as anti-clotting agents in diseases such as venousthrombosis, thrombotic coronary occlusion and other diseases involvingthrombi. For circulatory diseases, they have therapeutic utility inhypertension, peripheral vasopathies and cardiac disorders.

The following references include a more complete review of the chemical,physiological and pharmacological aspects of the prostaglandins: TheProstaglandins, Vol. I., P. Ramwell, Ed., New York, Plenum Press, 1973;Ann. N.Y. Acad. Sci., 180: 1-568 (1971); Higgins and Braunwald, J. Am.Med. Assnn. 53: 92-112 (1972); Osterling, Marozowich, and Roseman, J.Phar Sci., 61: 1861-1895 (1972); and Nakano, Resident and Staff Phys.,19: 92, 94-99, and 102-106 (1973).

SUMMARY OF THE INVENTION

Compounds of the formula ##STR15## wherein:

L is methylene, ethylene, or trimethylene;

K is ethylene or cis-vinylene;

M is carbonyl, α-hydroxymethylene, or β-hydroxymethylene, orβ-hydroxymethylene;

N is methylene or methine, provided that N is methine only if P ismethine and M is carbonyl;

P is methylene, ethylene, α-hydroxymethylene or methine, provided that Pis methine only if N is methine; and

R is carboxyl; hydroxymethylene, alkoxycarbonyl, the alkyl portion ofsaid alkoxycarbonyl being a lower alkyl, or a pharmacologicallyacceptable non-toxic carboxy salt., although not possessing the C-16 toC-20 chain segment, nonetheless have, in various instances, displayeddifferent types of biological activity.

Of the possible structures included within Formula III, thoserepresenting analogues of the A, E, and F prostaglandins constitutepreferred subgeneric classes. Specifically, limiting L to ethylene, M tocarbonyl, N and P to methine, and R to carboxyl, methoxycarbonyl, orethoxycarbonyl gives the depentyl PGA analogues. With the appropriatestereochemistry of the side chains, they have the general structure:##STR16##

With L, M, and R as above, but with N methylene and Pα-hydroxymethylene, the structure of Formula III then becomes thedepentyl analogues of the PGE compounds. These are encompassed by thegeneral structure: ##STR17##

However, with P methylene rather than α-hydroxymethylene, compoundsanalogous to the 11-deoxy-derivatives of the E family result. Thefollowing general structure represents these compounds: ##STR18##

Lastly, limiting L still to ethylene, N to methylene, M toα-hydroxymethylene or β-hydroxymethylene, P to α-hydroxymethylene givesthe depentyl PGF.sub.α or PGF.sub.β analogues, respectively. They havethe generalized structure: ##STR19##

Table I summarizes the reactions used to produce the depentyl analoguesof the prostaglandins. In general, the method commences by mixing thetrans-1-iodo-3-alkoxy-1-propene (VIII) with lithium metal or analkyllithium compound. The reaction should proceed in a dry aproticorganic solvent under an inert atmosphere at a temperature of about -78°to 0° C. The aprotic solvent, of couse, should not give off hydrogen,hydroxy, or ammonium radicals.

When using an alkyllithium (IXb) to substitute lithium for iodine inFormula VIII, the alkyl portion should have at least two carbon atoms.It should also be a lower alkyl moiety, that is one with no more thanfour carbon atoms.

The R-group on the iodopropene (VIII) serves to protect the hydroxylfunction as that molecule undergoes subsequent reaction. This, ofcourse, requires the R-group to remain stable to the alkyllithium andalkylcopper compounds that it will encounter.

On the other hand, after the completion of the desired reactions, a mildacid treatment should suffice to remove the R-group and restore thehydroxyl function. The mild acid employed should generally not affectthe structure of the molecule produced except to remove thehydroxyl-protecting group. Most carboxylic acids, and, in particular,oxalic, formic, or acetic acids, fall into this category. Thetetrahydropyran-2-yl and 1-ethoxyethyl radicals have shown themselves asvery suitable hydroxyl-protecting groups.

The lithiopropene (X) produced by the above reaction may then combinewith the hexamethylphosphorus triamide complex of copper(I) pentyne (XI)to produce the mixed cuprate reactant (XII). ##STR20## This reactiontakes place readily in a dry aprotic solvent at a temperature of about-78° to -20° C.

The copper reagent thus produced may then react, also in a dry aproticsolvent, with the 2-substituted-cyclopent-2-enone (XIII). The generalreaction involved has received discussion in Corey and Beames, J. Am.Chem. Soc., 94: 7210-7211 (1972); Sih, Price, Sood, Salomon, Peruzzotti,and Casey, J. Am. Chem. Soc., 94: 3643-3644 (1972); Sih, Solomon, PriceSood, and Peruzzotti, J. Am. Chem. Soc., 97: 857-865 (1975); and Sih,Heather, Sood, Price, Peruzzotti, Lee and Lee, J. Am. Chem. Soc., 97:865-974 (1975).

In Formula XIII, K and L have the same meaning as that given for thefinal prostaglandins above. P may be methylene, ethylene, α-OR" orα-OR", where R" is also a hydroxyl-protecting group having the sameproperties as stated above for R. R" in structure XIII may be aloweralkyl alkoxycarbonyl, OR"', again R"' represents ahydroxyl-protecting group with the same properties as R and R", above.

The reaction to attach the C-13 to C-15 segment of the depentylprostaglandin, above, commences at a temperature of about -78° to -20°C. It then proceeds to completion at a temperature of about -20° to +25°C.

The above reactions normally produce a depentyl analogue of the E classof prostaglandins. These may then undergo subsequent reaction to producethe analogues of the A and F classes, as illustrated in Table II, anddiscussed in Pike, Lincoln, and Schneider, J. Org. Chem., 11: 3552-3557(1969).

Specifically to formulate the analogue of PGA₁, which bears the name ofMethyl 15-Hydroxy-9-oxo-16,17,18,19,20-pentanorprosta-10,13E-dien-1oate(XVI), ##STR21## the depentyl PGE₁ (Methyl11α,15-Dihydroxy-9-oxo-16,17,18,19,20-pentanorprost-13E-en-1-oate (XV)is mixed with a mild carboxylic acid at a relatively high temperature ofabout 50° to 70° C. Using acetic acid also gives the 15-acetate (XVII).On the other hand, mixing the same depentyl analogue of PGE₁ with sodiumborohydride in a dry alcohol at about -20° to +25° C. will produce thedepentyl analogues of PGE₁α (XVIII) and PGF₁β (XIX).

DETAILED DESCRIPTION

Preparing the depentyl prostaglandin analogues according to the abovereactions requires various initial reactants. These include thetrans-1-iodo-3-hydroxy-1-propene (VIII) with a group protecting thehydroxy function, the hexamethylphosphorus triamide complex of copper(1) pentyne (XI) and the 2-substituted-cyclopent-2-enone (XIV). Thelast, where required, will also include a protected α-hydroxyl group onthe cyclopentenone portion.

The copper reagent (XI) prepares most easily. It results simply from themixing together of 0.407 g. (3.12 mmol) of copper(I)pentyne, preparedaccording to the teaching of C. E. Castro et al., J. Org. Chem., 31:4071 (1966), with 1.15 ml of hexamethylphosphorus triamide (from theAldrich Chemical Co., Inc.) dissolved in 8 ml of dry ether. Stirring thesolution together for about 15 minutes at about 25° C will produce thecopper reactant.

TRANS-1-iodo-3-protected hydroxy-1-propane (VIII)

Various protecting groups can adequately protect the hydroxyl functionat the C-3 site of the iodopropene. As discussed above, it must performthis protecting function during the reactions required to produce theprostaglandin analogue; it should also undergo facile removal with amild acid treatment. While the following preparation involves the use ofthe 1-ethoxyethoxy group, Formula XX, the tetrahydropyran-2-yl moietywould proceed in a similar fashion. ##STR22##

Specifically, a mixture of 5.82 ml (100 mmol) of propargyl alcohol(obtained from the Aldrich Chemical Co., Inc.) and 80 ml of dry heptanewas stirred under argon with ice-bath cooling as 25 ml (121 mmol) oftriisobutylaluminum (from the Ethyl Corp.) was added dropwise at a ratesuch that the internal temperature of the reaction mixture never wentabove 10° C. A 22 ml (123 mmol) portion of diisobutylaluminum hydride(also from the Ethyl Corp.) was then added, and the resultant solutionheated to 50° to 60° C for 3 hours. Distillation at 20 mm-Hg. removedthe solvent with the vacuum released with argon. The residue was cooledto 0° C and then slowly diluted with 100 ml of dry tetrahydrofuran. Theresultant solution was stirred at -78° C under argon as a solution of 62g of iodine in 120 ml of dry tetrahydrofuran was added dropwise.

After coming to room temperature, the dark solution was quenched by theslow dropwise addition of 150 ml of 20% sulfuric acid. An ice-bathmaintained the reaction mixture at about 20° to 30° C. The resultantmixture was diluted with 250 ml of water and extracted with 4 portionsof 250 ml of ethyl acetate.

The combined extracts were washed successively with saturated aqueoussodium bicarbonate, aqueous sodium thiosulfate and saturated aqueoussodium bicarbonate again. After the solution dried (Na₂ SO₄),evaporating the solvent in vacuo gave a dark oil. This oil was dissolvedin 25 ml of dry triethylamine and heated under argon at 85° to 95° C for23 hours. The excess triethylamine was removed by evaporation in vacuo.The residue was partitioned between ethyl acetate and 10% HCl. Theaqueous phase was extracted three more times with ethyl acetate. Thecombined extracts were washed with brine, dried (MgSO₄) and evaporatedin vacuo to yield 7.3 g of a dark oil. Distilling this crude product invacuo gave 4.2 g (22.8%) of pure trans-1-iodo-3-hydroxy-1-propene, whichhad the following physical chemical data:

Boiling point: 115° to 120° C (20 mm-Hg.);

NMR (CDCl₃): δ3.1 (1H, broad s), 4.07 (2H, d, J=4.5 Hz), 6.34 (1H, d,J=15 Hz), and 6.73 ppm (1H, d of t, J=15, 4.5 Hz);

IR (film): 920, 960, 1005, 1070, 1170, 1235, 1610, 2860, 2925 and 3100to 3600cm⁻¹ (broad).

A general description of this preparation has appeared in Sih, Heather,Peruzzotti, Price, Sood and Lee, J. Am. Chem. Soc., 95: 1676-1677(1973).

To protect the hydroxyl function, one drop of phosphorousoxychloride wasadded to a solution of 2.1 g of trans-1-iodo-3-hydroxy-1-propene in 5 mlof ethylvinyl ether under argon. The resultant solution remained at roomtemperature under argon for 20 hours. It was then diluted with ether andwashed with saturated aqueous sodium bicarbonate. The wash solution wasback extracted with ether. The combined extracts were dried (Na₂ SO₄)and evaporated in vacuo to yield 2.8 g of a yellow oil which was thendistilled in vacuo to yield 2.7 g of puretrans-1-iodo-3-(1-ethoxyethoxy)-1-propane (XX). In another run the samedistillation produced extensive decomposition. As this decomposition wasthought to be acid catalyzed, the product was subsequently distilledfrom a trace of anhydrous potassium carbonate. This reactant, used inpreparing the depentyl prostaglandin analogues displayed the followingphysical chemical data:

Boiling point: 115° to 120° C (20 mm-Hg.);

NMR (CDCl₃): δ 1.2 (3H, t, J=6.5 Hz.); 1.3 (3H, 3, J=5.3 Hz), 3.6 (2H,d, J=5.3 Hz), 3.6 (2H, complex), 3.95 (2H, d, J=4.5 Hz), 4.75 (1H, q,J=5.3 Hz), 6.17 (1H, d, J=14 Hz), and 6.75 ppm (1H, d of t, J=18.5 Hz);

IR (Film): 930, 1055, 1085, 1130, 1340, 1385, 1605, 2910, and 2980 cm⁻¹.

2-Substituted-cyclopent-2-enone and 2-Substituted-cyclohex-2-enone(XIII)

As Formula XIII suggests, this reactant will have a six-memberedcyclohexanone ring when P in the formula stands for ethylene. Afive-membered cyclopentanone ring results otherwise.

For the analogues of the prostaglandins of the A₁, E₁, or F₁ classes, Kin Formula XIII will again represent ethylene. For the E₂, A₂, and F₂classes, K will stand for cis-vinylene.

Typically, the C-2 site in the cyclopentanone portion of Formula XIIIhas a seven-membered chain attached to it. In that case, L in FormulaXIII stands for ethylene. Alternatively, the side chain may have six oreight conjoined carbon atoms when L represents methylene ortrimethylene, respectively. The preparation of the reactants with thesedifferent chain lengths proceeds in a similar fashion as theseven-membered side chain. Clearly, however, the starting linearmolecule which attaches to the cyclopentenone ring will have one feweror more carbon atom, as appropriate.

The specific reactants used in preparing the exemplary depentylprostaglandins below include 2-(6-carbomethoxyhexyl)-cyclopent-2-enone,2-(6-carbomethoxy-cis-2-hexenyl)-cyclopent-2-enone,2-(6-carbomethoxyhexyl)-4α-(tetrahydropyran-2-yloxy)-cyclopent-2-enone,and2-(6-carbomethoxy-cis-2-hexenyl)-4α-(tetrahydropyran-2-yloxy)-cyclopent-2-enone.These represent compounds whose preparation the literature describesfairly well. The preparation of the first compound appears in the twoarticles: Sih, Solomon, Price, Sood and Peruzzotti, Tetrahedron Let.,24: 2435-2437 (1972) and Sih et al., J. Am. Chem. Soc., 97: 857-865(1975). Grieco and Reap in J. Org. Chem., 38: 3413-3415 (1973) detailthe production of the second reactant above.

The preparation of the third utilized the compound2-(6-carbomethoxyhexyl)-4α-hydroxy-2-cyclopent-2-enone, the origin ofwhich has a discussion in Sih et al., J. Am. Chem. Soc., 95: 1676-1677(1973). The hydroxyl group on this compound, of course, remainssusceptible to attack in the reactions it undergoes. The article by Sihet al., J. Am. Chem. Soc., 97: 857-865 (1975), in the first column ofpage 862, describes how to protect the hydroxyl group through theaddition of the tetrahydropyran-2-yl group. In fact, the articleprotects the hydroxyl group in the ethyl ester of the reactant, asopposed to the methyl ester as used here.

The preparation of the last compound above follows the synthetic routedescribed in Heather, Sood, Price, Peruzzotti, Lee, Lee and Sih,Tetrahedron Let., 25: 2313-2316 (1973).

EXAMPLES EXAMPLE 1 dl-11-Deoxy-15-depentyl-PGE₁ [(±)15-Hydroxy-9-oxo-16,17, 18,19,20-pentanorprost-13E-en-1-oic acid] (XXI)##STR23##

A solution of 0.798 g (3.12 mmol) oftrans-1-ioxo-3-(1-ethoxyethoxy)-1-propen (XX) in 8 ml of dry ether wasstirred at -78° C under argon as 3.67 ml (6.24 mmol) of a solution oft-butyllithium (1.7M) in pentane was added via syringe. The resultantsolution was stirred for 2 hours at -78° C. It then received, viasyringe, a solution of 0.407 g (3.12 mmol) of copper(I)pentynesolubilized with 1.15 ml of hexamethylphosphoroustriamide in 8 ml of dryether. The resultant alkylcopper solution was stirred for 2 hours at-78° C.

A solution of 0.705 g (3.15 mmol) of2-(6-carbomethoxyhexyl)-cyclopent-2-enone in 5 ml of dry ether was thenadded dropwise to the alkylcopper solution. The resultant mixture wasstirred for 15 minutes at -78° C, then 1 hour at -20° C to -25° C, andthen for 15 minutes at 0° C. The addition of 5 ml of 20% aqueousammonium sulfate at 0° C quenched the reaction.

After diluting the resultant mixture with ether, 50 ml of cold 2%sulfuric acid was added. The resultant mixture was stirred vigorouslyand then filtered through diatomaceous earth (sold under the trademarkCelite® by the Johns Manville Products Company). The filter pad receiveda thorough rinsing with ether. The organic layer of the filtrate wasmixed with another portion of cold 2% sulfuric acid and then filteredagain. The process was repeated until no additional solid appeared uponthe addition of 2% sulfuric acid.

The combined aqueous wash layers were back extracted with ether severaltimes. The combined extracts were washed with brine and saturatedaqueous sodium bicarbonate. They were then dried (MgSO₄) and evaporatedin vacuo. After dissolving in 20 ml of acetic acid-water-tetrahydrofuran(65:35:10), the resultant yellow oil remained under argon for 16 hours.Evaporation in vacuo removed the solvent, and ether dissolved theresidue. The solution was washed twice with saturated aqueous sodiumbicarbonate, and the wash solution twice back extracted with ether. Thecombined extracts were dried (MgSO₄) and evaporated in vacuo to give 0.7g of crudedl-2α-(6-carbomethoxyhexyl)-3β-(3-hydroxy-1-trans-propenyl)-cyclopentanoneas a yellow oil.

This oil dissolved in 10 ml of 5% potassium hydroxide in methanol-water(3:1) and remained at room temperature under argon for 3 hours. Again,the solvent was removed by evaporation in vacuo, and the residuedissolved in water and extracted with ethyl acetate. The extract waswashed with water, and then was discarded. The combined aqueous phaseswere acidified with 10% hydrochloric acid and extracted several timeswith ethyl acetate. These combined extracts were dried (MgSO₄) andevaporated in vacuo. The yield was 0.742 g of crude dl-deoxy-15-depentylPGE₁ (XXI) as a yellow oil. This crude product was purified bychromatography on silica acid-Celite® (80:20) using benzene-ethylacetate gradient elution to give 208.4 mgm (24.9%) of pure XXI as afaint yellow oil. This compound displayed the following physical data:

NMR CDCl₃): δ 0.8-3.0 (18H, m), 4.2 (2H, broad d, J=3.5 Hz), 5.7 (2H, m)and 7.55 ppm (2H, broad s);

IR (film): 970, 1160, 1405, 1700-1740 (broad) 2860, 2930, and 2400-3600cm⁻¹ (broad);

Mass Spectrum (70 eV): m/e 268(p), 250 (p-H₂ O), 232 (p-2H₂ O), 219,193, 140, 122, 109 and others below 100.

EXAMPLE 2 dl-11-Deoxy-15-depentyl-PGE₂ -Methyl ester [(±) Methyl15-Hydroxy-9-oxo-16,17,18,19,20-pentanorprosta-5Z,13E-dien-1-oate](XXII) ##STR24##

A solution of 0.773 g (3.02 mmol) oftrans-1-iodo-3-(1-ethoxyethoxy)-1-propen (XX) in 3 ml of dry ether wasstirred at -78° C under argon as a syringe added 3.55 ml (6.04 mmol) ofa solution of t-butyllithium (1.7M) in pentane. The resultant solutionwas stirred for 2.3 hours at -78° C. To this first solution was thenadded dropwise a solution of 398 mgm (3.05 mmol) of copper(I)pentynesolubilized in 8 ml of ether with 1.15 ml ofhexamethylphosphoroustriamide. The resultant mixtue was stirred for 2.5hours at -78° C before a solution of 677 mg (3.05 mmol) of2-(6-carbomethoxy-cis-2-hexenyl)-cyclopent-2-enone in 8 ml of ether wasadded dropwise.

After warming to -20° C to -25° C, the resultant mixture was stirred for2 hours. The dropwise addition of several ml of 20% aqueous ammoniumsulfate then quenched it. The resultant mixture was diluted with etherand then stirred in an ice bath as 100 ml of 2% aqueous sulfuric acidwas added slowly.

The resultant mixture was filtered through Celite®. The filter pad wasrinsed well with ether. The filtrate phases were separated, and theaqueous phase back extracted twice with ether. The combined extract waswashed with brine and then saturated aqueous sodium bicarbonate. It wasdried (MgSO₄) and evaporated in vacuo.

After dissolving in 25 ml of acetic acid-water-tetrahydrofuran(65:35:10), the resultant oily residue remained at room temperatureovernight. Evaporation in vacuo removed the solvent and the residue wasdissolved in ethyl acetate and washed with saturated aqueous sodiumbicarbonate. Ethyl acetate twice back extracted the wash solution. Thecombined extract was dried (MgSO₄) and evaporated in vacuo to yield0.791 g of crude (XXII). Purification by column chromatography onsilicic acid-Celite® (85:15) using benzene-ethyl acetate gradientelution gave 278 mgm of pure (XXII). It had the following physicalproperties:

NMR (CDCl₃): δ0.8-3.0 (14H, complex), 3.73 (3H, s), 4.2 (2H, broad d,J=3.5 Hz), 5.5 (2H, M), and 5.78 ppm (2H, m);

IR (film): 975, 1040, 1060, 1440, 1635, 2875, 2590 and 3100-3700 cm⁻¹(broad).

EXAMPLE 3 15-Depentyl-PGE₁ Methyl ester [Methyl11α,15-Dihydroxy-9-oxo-16,17,18,19,20-pentanorprost-13E-en-1-oate] (XV).##STR25##

A solution of 2.45 g (9.57 mmol) oftrans-1-iodo-3-(1-ethoxyethoxy)-1-propene in 25 ml of dry ether wasstirred under argon at -78° as 11.3 ml (19.2 mmol) of a solution oft-butyllithium (1.7 M) in pentane was added dropwise. The resultantmixture was stirred for 2 hours at -78° C. Another solution was preparedby stirring 1.037 g (10.0 mmol) of copper(I)pentyne in 20 ml of etherwith 3.67 ml of hexamethylphosphorous triamide until homogeneous.

This solubilized copper(I)pentyne solution was then added dropwise tothe above alkenllithium solution with stirring at -78° C. The resultantmixture was stirred at -78° C for an additional 2 hours.

A third solution of 3.22 g (9.91 mmol) of2-(6-carbomethoxyhexyl)-4α-tetrahydropyran-2-yloxy)-cyclopent-2-enone in20 ml of ether was added dropwise with vigorous stirring to the abovemixture. The resultant slurry then incurred stirring for 0.5 hour at-78° C and then at -23° C for 2 hours. The additin of 5 ml of 20%aqueous ammonium chloride at -20° C then quenched it.

The resultant mixture received dilution with ether and then stirring inan ice bath during the slow addition of 2% sulfuric acid. The resultantmixture was filtered through Celite® and the filter pad rinsed severaltimes with ether. After the separation of the filtrate's phases, afurther portion of 2% sulfuric acid washed the organic phase. Filteringthe mixture again through Celite® removed precipitated copper(I)pentyne.

The resultant phases were separated and the aqueous phase back extractedseveral times with ether. The combined ether extracts were washed withbrine and then satuated aqueous sodium bicarbonate. They were dried(MgSO₄) and then evaporated in vacuo to yield 4.4 g of a yellow oil.

This oil, after dissolving in 45 ml of acetic acid-water-tetrahydrofuran(65:35:10), remained for 20 hours at room temperature under argon.Evaporation in vacuo removed the solvent, and the residue was dissolvedin ethyl acetate and washed with saturated aqueous sodium bicarbonatetwice. The combined wash solution was back extracted three times withethyl acetate. The combined extract was dried (MgSO₄) and evaporated invacuo to yield 3.65 g of crude 15-depentyl-PGE₁ -methyl ester (XV).Column chromatography on silicic acid-Celite® (85:15) usingbenzene-ethyl acetate gradient elution purified the residue to yield870.6 mg of pure (XV) elution purified the residue to yield 870.6 mg ofpure (XV) as a waxy faint yellow solid with the following properties:

NMR (CDCl₃): δ 0.8-3.0 (16H, complex), 3.6 (3H, s), 4.1 (5H, broad s)and 5.77 ppm (2H, m);

IR (film): 965, 1073, 1155, 1205, 1440, 1738, 2860, 2930, and 2930-3700cm⁻¹ (broad);

Mass Spectrum (70 eV): m/e 280 (p-H₂ O), 262 (p-H₂ O), 248 (p-H₂ O)-CH₃OH), 236, 321, 204, 194, 177, 149, 138, 120, 107, and others below 100.

EXAMPLE 4 15-Depentyl-PGE₂ -Methyl ester [Methyl11α,15-Dihydroxy-9-oxo-16,17,18,19,20-pentanorprosta-5Z,13E-dien-1-oate](XXIII). ##STR26##

A solution of 384 mgm (1.50 mmol) oftrans-1-iodo-3-(1-ethoxyethoxy)-1-propene in 4 ml of dry ether wasstirred at -78° C under argon during the dropwise addition of 2.0 ml(3.56 mmol) of a solution of t-butyllithium in pentane (1.8M). Theresultant mixture underwent stirring at -78° C for 2 hours. A slurry of197 mg (1.51 mmol) of copper(I)pentyne in 4 ml of dry ether was stirredwith 0.55 ml of hexamethylphosphorus triamide under argon untilhomogeneous and then transferred dropwise via syringe to the abovealkenyllithium solution. The resultant yellow solution was stirred for 1hour at -78° C.

A third solution of 437 mgm (1.36 mmol) of2-(6-carbomethoxy-cis-2-hexenyl)4α-(tetrahydropyran-2-yloxy)-cyclopent-2-enone in 4 ml of dry ether wasadded dropwise to the above yellow solution. The resultant slurryreceived a brief stirring at -78° C, then at -15° to -20° C for 1.5hours, and then at 0° C for 0.5 hour. The addition of severalmilliliters of 20 % aqueous ammonium sulfate solution at 0° C quenchedthe reaction.

The resultant mixture was diluted with ether and then stirred in an icebath through the addition of 50 ml of 2% aqueoius sulfuric acid. Theresultant mixture was stirred vigorously and then filtered throughCelite®. The filter pad was washed several times with ether, the phasesseparated, and the aqueous phase back extracted twice with ether. Thecombined extract was washed with brine and saturated aqueous sodiumbicarbonate, dried (MgSO₄) and evaporated in vacuo. Twenty-five ml ofacetic acid-water-tetrahydrofuran (65:35:10) dissolved the residue whichthen remained under argon at room temperature for 20 hours. Evaporationin vacuo removed the solvent, and ethyl acetate dissolved the residue.Saturated aqueous sodium bicarbonate washed the solution and the washliquid was back extracted twice with ethyl acetate. The combined extractunderwent drying (MgSO₄) and evaporation in vacuo. Chromatography onsilicic acid-Celite® (85:15) using benzene-ethyl acetate gradientelution purified the 0.446 g of resulting residue to yield 76.5 mgm ofthe 15-depentyl-PGE₂ -methyl ester (XXIII) as a faintly yellow oil. Thecompound had the following characteristics:

NMR (CDCl₃): δ 1.0-3.0 (12H, complex), 3.6 (2H, broad s), 3.65 (3H, s),4.15 (3H, m), 5.4 (2H, broad s), and 5.75 ppm (2H, m);

IR (film): 975, 998, 1082, 1160, 1250, 1440, 1740, 2850, 2940, and3100-3700 cm⁻¹ (broad s).

EXAMPLE 5 15-Depentyl-PGA₁ -Methyl ester [Methyl15-Hydroxy-9-oxo-16,17,18,19,20-pentanorprosta-10,13E-dien-1-oate] (XIV)and 15-Depentyl-PGA₁ -Methyl ester-15-Acetate [Methyl15-Acetoxy-9-oxo-16,17,18,19,20-pentanorprosta-10,13E-dien-1-oate](XVII).

A solution of 149 mgm of 15-depentyl-PGE₁ -methyl ester, prepared as inExample 3, in 4.5 ml of acetic acid and 0.5 ml of water was stirred at60° C under argon for 16 hours. The resultant yellow solution wasevaporated in vacuo. The residue was dissolved in ether and washed withsaturated aqueous sodium bicarbonate. Ether twice back extracted thewash solution. Drying (MgSO₄) and evaporated the combined extracts invacuo yielded 142 mgm of an orange oil. Purifying the residue bypreparative thin layer chromatography on a 20 × 20 cm × 2 mm silica gelPF254 plate by eluting with ether gave two major U.V.-active bands whichether then washed from the silica.

The yield of 76.3 mgm of the 15-depentyl-PGA₁ -methyl ester (XVI) hadthe following physical data:

NMR (CDCl₃): δ 0.8-2.5 (14H, m), 3.3 (1H, m), 3.68 (3H, s), 4.13 (2H, d,J=3.5 Hz), 5.7 (2H, m), 6.18 (1H, m) and 7.5 ppm (1H, m);

IR (film): 800, 974, 1010, 1095, 1180, 1200, 1350, 1440, 1590, 1710,1740, 2860, 2940, and 3100-3700 cm⁻¹ (broad).

Mass Spectrum (70 eV): m/e 280 (p), 262 (p-H₂ O), 248 (p-CH₃ OH), 21(p-H₂ O-CH₃ OH), 138, 133, 120, 107, and others below 100.

The second major band (higher R_(f)) produced 24.0 mgm of15-depentyl-PGA₁ -methyl ester-15-acetate (XVII), which displayed thefollowing characteristics:

NMR (CDCl₃): δ 0.8-2.5 (14H, m), 2.07 (3H, s), 3.3 1H, m), 3.68 (3H, s),4.52 (2H, m), 5.7 (2H, m), 6.15 (1H, m) and 7.5 ppm (1H, m).

IR (film): 800, 974, 1010, 1095, 1180, 1200, 1350, 1440, 1590, 1710,1740, 2860, and 2940 cm⁻¹.

EXAMPLES 6 and 7 15-Depentyl-PGF₁α -Methyl ester [Methyl16,17,18,19,20-Pentanor-9α,11α,15-trihydroxyprost-13E-en-1-oate] (XVIII)and 15-Depenty-PGF₁β -Methyl ester [Methyl16,17,18,19,20-Pentanor-9β,11α,15-trihydroxyprost-13E-en-1-oate] (XIX).

A solution of 482 mgm of 15-depentyl-PGE₁ -methyl ester (XV), preparedas in Example 3, in 25 ml of dry methanol was stirred at 0° C during theaddition, over 10 minutes, of a total of 1.01 g of sodium borohydride inseveral portions. The resultant solution was stirred for 1 hour at 0° Cand then 1 hour at room temperature. Evaporation in vacuo removed thesolvent. The white residue was partitioned between ethyl acetate andbrine. After separating the phases, ethyl acetate extracted the acqueouslayer three times. Drying (MgSO₄) and evaporating in vacuo yielded 420.8mgm of a clear oil. Separating this residue into components by columnchromatography on silicic acid-Celite (85:15) using benzene-ethylacetate gradient elution gave 105.1 mgm of the less polar15-depentyl-PGE₁α -methyl ester (XVIII) (R_(f) 0.13, tlc) and 141.2 mgmof the more polar 15-depentyl-PGF₁β -methyl ester (XIX) (R_(f) 0.10,tlc). Also obtained was 7.5 mgm of a mixed fraction.

These thin-layer chromatography determinations used a solvent preparedby shaking thoroughly a mixture of 1100 ml of ethyl acetate, 200 ml ofacetic acid, 500 ml of isooctane and 1000 ml of water and allowing themto settle for several hours. The lower phase is removed and discarded.The upper phase is used as the developing solvent. After developing withthis solvent, the tlc plate is air dried with brief warming.

To allow visualization of the tlc results, a solution is prepared bydiluting an 84 ml portion of concentrated sulfuric acid to 1 liter withdeionized water. A 30 g portion of ceric sulfate is slowly stirred intothe dilute acid. The tlc plate then receives a spray of this acidsolution and a heating at 250° C for approximately 1 minute. Theprostaglandins appear as brown spots on the plate as a result of thetreatment.

The PGF₁α (XVIII) and PGF₁β (XIX) depentyl analogues have the followingidentical spectra:

NMR (CDCl₃): δ0.7-2.5 (16H, complex), 3.6 (3H, s), 4.17 (7H, broad m),and 5.65 ppm (2H, m).

IR (film): 965, 995, 1040, 1080, 1100, 1167, 1195, 1440, 1720, 1735,2850, 2920, and 3100-3600 cm⁻¹ (broad).

Mass Spectrum (70 eV): m/e 282 (p-H₂ O), 251 (p-H₂ O-CH₃ O), 246(p-3H₂), 233, 210, 178, 150, 140, 136, 121, 107 and other below 100.

EXAMPLE 8 Biological Activity

The compounds from Example 1 through 7 above underwent a variety oftests to determine their biological activity. The resports belowresulted from tests in which the compounds displayed the most consistentactivity, as a group.

The other experiments undertaken, in general, produced less or noactivity for most of the compounds. Some of these tests did produce someactivity for one or more analogues. This latter group of tests includedthe effects of the depentyl prostaglandin analogues on:

(a) the rat uterus in vitro;

(b) the guinea pig trachea in vitro;

(c) blood pressure and heart rate in the anesthetized cat;

(d) blood pressure in the hypertensive rat;

(e) gastric secretions in the rat; and

(f) the action of the natural prostaglandins on the guinea pig ileum invitro.

Example 8A Cascade Assay

The smooth muscle stimulant effects of test compounds are determinedsimultaneously in four different tissues which are known to becontracted by naturally occurring prostaglandins. Segments of ratstomach fundus, rat colon, chick rectum and rabbit aortic strip areobtained as described by Vane, Brit. J. Pharmacol., 12: 344 (1957);Regoli and Vane, Brit. J. Pharmacol., 23: 351 (1964); Mann and West,Brit. J. Pharmacol., 5, 173 (1950); and Furchgott and Bhadrakom, J.Pharmacol. Exper. Ther., 108: 129 (1953).

One end of each preparation is tied to the bottom of a 10 ml tissuechamber and the other to a Grass Ft-03 force displacement transducer forcontinuous tension recording. The stomach, colon and rectum segments arestretched to an initial tension of 1 g, while the aortic strip issubjected to 4 g. All preparations remain undisturbed for 1 hour. Thechambers possess an external jacket in which water at 40° C circulatesto keep the tissues warm. Preparations are arranged one beneath theother, aorta, stomach, colon and rectum in descending order.

Provision is made for bathing the four tissues successively so that theyare superfused (Gadum, Brit. J. Pharmacol., 6: 321 (1953) with the samefluid. This consists of Krebs bicarbonate solution bubbled with amixture of 95% 0₂ and 5% CO₂, warmed at 37° C and containing atropinesulphate (0.1 mcgm/ml), phenoxybenzamine hydrochloride (0.1 mcgm/ml),propranolol hydrochloride (3.0 mcgm/ml) methylsergide maleate (0.2mcgm/ml) and brompheniramine maleate (0.1 mcgm/ml), in order toeliminate the possibility of smooth muscle responses being due tostimulation of cholinergic, adrenergic, serotonin or histaminereceptors. The fluid, circulated by means of a roller pump, drips overthe preparations at a rate of 10 ml/minute.

Test compounds are diluted from stock solutions in order to administerquantities ranging from 0.001 to 100,000 ngm in a volume of 0.5 ml. Thedrugs are applied by dripping on the uppermost tissue, at intervals of10 to 20 minutes. Maximal increases in tension after each dose aremeasured and results used to plot dose-response curves. The results forthe rat stomach fundus appear in Table III.

EXAMPLE 8B Gastric Secretion in the Rat

Utilizing the procedure of Lepman, J. Pharm. Pharmacol., 21: 355 (1968),rats of one sex weighing 150 to 200 g are randomly divided into groupsof sic animals each and fasted for the 48 hours previous to theexperiments, water being available ad libitum. The animals areanesthetized with ether, the abdomen opened through a midline incision,and the pylorous ligated. Test compounds are diluted from stock solutionin order to administer a dose of 1.5 mg/kg in a volume equivalent to 1ml/kg. Subcutaneous injections are applied immediately after surgery andagain 2 hours later to administer a total dose of 3.0 mg/kg. Solutionswith phosphate buffer, as recommended by Lee, Bianchi, Mollison, and

                                      Table III                                   __________________________________________________________________________    Results of Cascade Analysis for Rat Stomach Fundus - G Tension                Depentyl Analogue                                                                             11-Deoxy   11-Deoxy                                           Dose ngm.  PGE.sub.1                                                                          PGE.sub.1                                                                           PGE.sub.2                                                                          PGE.sub.2                                                                          PGF.sub.1α                                                                   PGF.sub.1β                          __________________________________________________________________________    0.001      0.5  0.4   0.1  0.3  0.5  0.4                                      0.01       0.5  0.4   0.3  0.3  0.4  0.5                                      0.1        0.4  0.4   0.3  0.3  0.6  0.6                                      1.0        0.5  0.4   0.3  0.6  0.5  0.4                                      10         0.5  0.5   0.3  0.5  0.5  0.4                                      100        0.5  0.5   0.3  1.0  0.5  0.5                                      1,000      3.2  0.5   0.3  0.7  0.5  0.4                                      10,000     4.2  0.5   0.6  2.2  0.5  0.4                                      100,000    5.8  2.6   1.0  3.2  0.5  0.3                                      __________________________________________________________________________

Hansen, J. Prostaglandins, 3: 29 (1973), insure adequate stability ofdrugs at the subcutaneous depot. Each compound is tested in one group ofrats; an additional control group receives only the vehicle.

Four hours after pyloric ligation, the animals are killed with ether,the cardias ligated and the stomachs removed. The volume of gastricsecretion is measured and the contents centrifuges at 5000 rpm for 10minutes. Total acid in the supernatant is titrated against a 0.1 Nsodium hydroxide solution and the amount expressed in mEq. Volume andtotal acid values of the treated group are compared with those of thecontrols by the t test. The results appear in Table IV.

EXAMPLE 8C

Inhibition of Human Platelet Aggregation

The ability of test compounds to inhibit platelet aggregation wasdetermined by a modification of the turbidometric technique of Born inNature, 194: 927 (1962). Blood, collected from human volunteers who hadnot ingested aspirin or aspirin-containing products within the precedingtwo weeks in heparinized containers, was allowed to settle for one hour.The platelet rich plasma (PRP) supernates were collected and pooled.Siliconized glassware was used throughout.

In the assay, 1.9 ml of the PRP and 0.2 ml of the test compound at theappropriate concentration (0.001 to 100 mcgm), or 0.2 ml of distilledwater as a control, were placed in sample cuvettes.

                  Table IV                                                        ______________________________________                                        Results for Gastric Secretion in the Rat                                      Depentyl    Volume        Total Acid                                          Analogue    Change-%      Change-%                                            ______________________________________                                        PGA.sub.1   +19           +22                                                 PGE.sub.1   -25           -30                                                 11-Deoxy    -36 to -10    -57 to -14                                          PGE.sub.1                                                                     PGE.sub.2   -14            -9                                                 11-Deoxy    -24           -35                                                 PGE.sub.2                                                                     PGF.sub.1α                                                                          -38           -41                                                 PGF.sub.1β                                                                            +23*          +19*                                               ______________________________________                                         *Determinations made at six rather than four hours after surgery.        

The cuvettes were placed in a 37° C incubation block for 15 minutes andthen in a spectrophotometer linked to a strip chart recorder. After 30to 60 seconds, 0.2 ml of a solution, prepared by diluting a calf skincollagen solution (from Worthington Biochemical) 1:9 with Tyrodes'Solution was added to each cuvette. A decrease in optical densityevidenced platelet aggregation.

The calculation of the degree of inhibition of platelet aggregationexhibited by each concentration of test compound followed the method ofCaprino, Borrelli, and Falchetti, Arzneim-Forsch, 23: 1277 (1973). Theresults appear in Table V.

                  Table V                                                         ______________________________________                                        Results of Inhibition of Human Platelet Aggregation-%                         Depentyl Analogue                                                             Dose mcgm   PGE.sub.1                                                                             PGE.sub.2                                                                             11-Deoxy                                                                             PGF.sub.1α                                                                    PGF.sub.1β                      ______________________________________                                        0.001       29      2       2      5     30                                   0.01        17      5       2      2     19                                   0.1         24      7       -9     7     24                                   1.0         19      -2      2      15    78                                   10          19      5       -6     22    26                                   100         19      2       -4     8      4                                   ______________________________________                                    

What is claimed is:
 1. A compound of the formula, ##STR27## wherein: Lis methylene, ethylene, or trimethylene;K is ethylene or; M is carbonyl;N is methine; P is methine; and R is carboxyl; alkoxycarbonyl, the alkylportion of said alkoxycarbonyl being a lower alkyl radical; or apharmacologically acceptable non-toxic carboxyl salt.
 2. The compound asin claim 1, 15-depentyl-PGA₁ methyl ester.